Therapy of toxoplasma encephalitis in AIDS patients requires long-term administration of antitoxoplasma agents to adequately treat the infection and prevent relapse. There are very few regimens that have demonstrated efficacy in treating toxoplasmosis. The best evaluated regimen is a combination of pyrimethamine plus sulfadiazine. Unfortunately, this regimen is associated with a high incidence of adverse reactions in MDS patients, frequently requiring discontinuation of therapy The combination of pyrimethamine and clindamycin also appears effective but again is associated with a high incidence of adverse reactions. Atovaquone is a hydroxynaphthoquinone with very effective anti-protozoal, including anti- toxoplasma and anti-malaria, activity in vitro and in animal models of infection. We have completed a study to provide a preliminary evaluation of the efficacy of atovaquone in the treatment of toxoplasmosis in AIDS patients. This study initially began with treatment with atovaquone as a single agent. Eight patients were enrolled, seven of whom improved and one of whom remained stable. Two patients ultimately relapsed. The remainder died from AIDS-related complications with no evidence of relapse during the follow-up period of up to sixty weeks. Subsequently, based on in vitro studies demonstrating synergy between atovaquone and pyrimethamine in animal models, we evaluated this combination in AIDS patients with toxoplasmosis. Six patients enrolled in this phase of the study. Two patients did not respond; both had low serum atovaquone levels. The remaining four responded; one patient continued on therapy for approximately 16 months with sustained improvement. Three patients died from AIDS-related complications. Thus, this study, which is now terminated, demonstrated that atovaquone alone or combined with pyrimethamine, is an active agent in the treatment of toxoplasmosis. Additional trials comparing atovaquone with standard therapies are thus warranted.